Uracil thioureas

ABSTRACT

WHEREIN X is selected from the group consisting of O and S, and wherein R is selected from the group consisting of lower alkyl having from one to four carbon atoms, allyl, methallyl and phenyl. Said compounds are useful as central nervous system antidepressants.   Uracil thioureas having the general formula

Unite States Patent Berger et a1.

[ 51 Aug. 28. 1973 URACIL THIOUREAS Inventors: Arthur Berger, Skokie, 111.; Edeltraut E. Borgaes, Sindelfingen, Germany Assignee: Baxter Laboratories, Inc., Morton Grove, Ill.

Filed: Dec. 6, 1971 Appl. No.: 205,328

Related US. Application Data Continuation of Ser. No. 849,890, Aug. 13, I969, abandoned.

US. Cl. 260/2565 R, 424/251 Int. Cl C07d 51/38 Field of Search ..260/25 6.5 R

References Cited FOREIGN PATENTS OR APPLICATIONS 1,219,489

6/1966 Germany Primary ExaminerA1ex Maze] Assistant Examiner-R. V. Rush Attorney-Walter C. Kehm [57] ABSTRACT Uracil thioureas having the general formula 12 Claims, No Drawings URACIL THIOUREAS This is a continuation of application Ser. No. 849,890, filed Aug. 13, 1969, now abandoned.

The present invention relates to novel organic uracil thioureas. More particularly, this invention relates to ring substituted uracil thioureas having the general formula:

(IJHa wherein X is selected from the group consisting of O and S, and wherein R is selected from the group consisting of lower alkyl having from one to about four carbon atoms, allyl, methallyl and phenyl.

The compounds of the present invention have been found to have potent central nervous system antidepressant activity in animals. The ability of these compounds to revive animals given large doses of barbiturates have been shown in mice, rabbits and dogs. As such, the compounds of the present invention are useful agents for these and other animals as narcotic, barbiturate and anesthetic antagonists and as psychomotor and respiratory stimulants. These compounds are new compounds which have not been described heretofore in the literature and have unique barbiturate antagonist properties.

Certain 5-substituted positional isomers of the present compounds have been described heretofore as having cytostatic properties by Kumar, German Pat. 1,219,489. However, the S-substituted uracil thioureas were found to be inactive central nervous system antidepressants.

The synthesis of the novel uracil thioureas of the present invention can be effected by reacting 6-aminol ,3-dimethyluracil or 6-amino-l ,3-dimethyl-2- thiouracil with an appropriate isothiocyanate. This synthesis is facilitated by reaction in the presence of a mutual solvent such as an amide, for example, dimethylformamide, or a sulfoxide, for example, dimethylsulfoxide.

The general reaction can be described by the following equation:

wherein X and R are as previously defined.

Illustrative of the isothiocyanates which can be used in the above reaction are the methyl, ethyl, n-propyl,

isopropyl, n-butyl, isobutyl, allyl, methallyl and phenyl isothiocyanates and the like. The isothiocyanate rcagents are generally available commercially or can be made by conventional procedures, for example, by reaction of an amine, CS, and NaOH as described in Organic Syntheses, Coll. Vol. 111, p. 599 (1955), John Wiley & Sons, Inc., New York and London.

The compound 6-amino-l,3-dimethyluracil also is generally available commercially or can be made by conventional procedures, for example, by reaction of 1,3-dimethylurea with ethyl cyanoacetate as described by Traube, Ann., Vol. 432, p. 281 (1923).

The corresponding 6-amino- 1 ,3-dimethyl-2- thiouracil can also be made by conventional procedures, for example, by reaction of NN'- dimethylthiourea with cyanoacetic acid in acetic anhydride and acetic acid as described by Wooldridge and Stack, J. Chem. Socy. 1962, pp. 1863-8 at 1865, and by Speer and Raymond, J. Am. Chem. Socy., Vol. 75, pp. 114-115 (1953).

Although specific methods of preparation of the novel uracil thioureas of the present invention are described herein, it will be understood that these compounds are not limited to these specific methods of preparation. For example, an alternative method of preparation consists of methylating the ring unsubstituted uracil thiourea. Other methods of preparation of these compounds can be devised by those skilled in the art.

The novel compounds of the present invention have been administered both intravenously (iv) and intraperitoneally (i.p.) in suspensions of pectin and gum acacia solutions and in alcohol-water solutions. These routes of administration as well as the oral route of administration can be used. Other methods of administration will be apparent to those skilled in the art.

Effective barbiturate antagonist dosages can range from about one to 1,000 mg. per kg. of body weight and can take the form of tablets, powders, capsules, elixers and the like dosage forms in admixture with common solid and liquid diluents, carriers and adjuvants such as, for example, cornstarch, lactose, talc, stearic acid, magnesium stearate, gelatin, acacia and locust bean gums, alcohol, water, vegetable oils and the like materials. Other effective dosages of the novel compounds can be determined by reference to the specific examples set forth hereinafter. It has been unexpectedly found that high dosages of these compounds lose their toxicity in the presence of the active barbiturates and thus appear to be less toxic in the presence than in the absence of barbiturates.

The following examples will further illustrate the present invention although the invention is not limited to these specific examples. All percentages and parts herein are on a weight basis unless otherwise specified.

EXAMPLE I Synthesis of l-(2,4-Diketo-1,3-Dimethyl-1,2,3,4- Tetrahydro-pyn'midin-6-yl)-3-Methyl-2-Thiourea. A mixture of 31.0 grams (0.20 mole) of 6-amino-l,3- dimethyluracil and 20.0 grams (0.27 mole) of methyl isothiocyanate in 400 ml. of dimethylformamide was heated under reflux for 2 hours after the reaction mixture had become clear for a total reaction time of 2.5 to 3 hours. The mixture was allowed to cool to about room temperature and then poured into chopped ice. The precipitate was collected and recrystallized from methanol with decolorizing carbon treatment. The

yield was 3 l .1 grams (68% of the theoretical) of light yellow crystals of l-(2,4-diketo-l,3-dimethyl-1,2,3,4- tetrahydropyrimidin-tS-yl)-3-methyl-2-thiourea, m.p. 230-1C.

EXAMPLE [I Systhesis of l-n-Butyl-3-(2,4-Diketo-1,B-Dimethyl- 1,2,3,4-tetrahydropyrimidin-6-yl)-2-Thiourea. A mixture of 31.0 grams (0.2 mole) of 6-amino-l,3- dimethyluracil and 30 ml. (excess) of butyl isothiocyanate in 400 ml. of dimethylformamide was heated at just below the reflux temperature for 1.5 hours. The reaction mixture was cooled to about 50C and then poured into crushed ice. A light yellow precipitate formed immediately, was collected on a filter and crystallized from methanol. The light yellow crystals of lbutyl-3-(2,4-diketo-l,3-dimethyl-1,2,3,4- tetrahydropyrimidin-6-yl)-2-thiourea, m.p. 133-4C, weighed 42.6 grams (78.8% of the theoretical) after drying.

Other examples of the uracil thioureas of the present invention were synthesized according to the procedure of the above examples. The analytical data determined for these compounds are set forth in the following table:

LII

procedure of Miller et al., Proc. Socy. Exper. B101. and Med, Vol. 57, p. 261 (1944). The lethal dose of the barbiturate which was administrated was the LD (the dose required to kill at least 9 of every 10 mice), or 126 mg./kilo of body weight.

Table II BARBX'I'URATE mxoomsr DATA ON URACIL THIOUREAS, mgJkg. 1N MICE TABLE I.ANALYTICAL DATA ON URACIL THIOUREAS 5 X= 3 |JNHC s NHR CHaN\ /CH Analysis. percent Melting Calculated Found point. Empirical X equals R equals G. formula C H N S C H N S 230-1 CSHllNlOZS 42.09 5.30 21.54 11.05 42.44 5.33 174-5 CQI'IilN-iOaS 44.01 5. 13.23 44.81 5.31 mm C1oH14N1OzS 47. 2a 5.55 12.61 .04 5.67 19-15 CmHiiNiOaS +1.42 5. .85 5.6-1 169-71 cmH sN-iozs 46. 36 6. 1. 6. 20 155-5 C10H1N402S 16. 86 6. (i. 27 150-2 CulIwNlOzS 41). 23 6. 6. 14 140-1 C11H1EN4O2S 48.87 6. 6.85 1334 01.111.01.018 18.87 6. 6.64 212-4 CiJHiiNiOQS 53. 78 4. 4. 82

The desirable central nervous system anti-depressant Table 111 h il ureas of this invention are puropertleg 8f the urac thiof h d REFERENCE CSN 1 ustrate y t e activity 0 t ese compoun s in pro- IANTLDEPRESSANTS (mg'lkg. tectmg mice against lethal doses of pentobarbital N In mice) dium (barbiturate antagonist activity). These illustra- 50 23 52 EQ 'fg' t1ve results are shown in the following Tables 11 and lll Bemigride sold 36 24 1.5 in which the compounds of the present invention are "gfgfg fgff compared with seven reference central nervous system Penetylene- 90 39 2.3 anti-depressants. In this comparison, which is a modifimm] 501d the trademark cation of the procedure reported by Kimura and R1ch- RITAUN ards, Arch. Intern. Pharmacodyn, Vol. 110, pp. 29-42 Meihylphenidate inactive t (1957), the ability of the test compound to reverse a g gggg i lethal dose of barbiturate is determined. The life or Rl'raLIN. 10-150 death of the test animals following administration of a Emamvan 37 under the trademark lethal dose of the barbiturate and then a trial dose of 0 EMIVAN 10.200 the test compound is used as the end point to provide cafi'eine Citrate 5 0 at the values given in the tables as the effective BlkD Nikethamide 245 ina'cfive a (med1an barbiturate antagonist dose). The margin of 150-300 safety of the test compound is shown by the ratio of the LD (median lethal dose) to the efi'ective barbiturate antagonist dose.

In this procedure, the LD 's and BAD s were determined by subjecting the mice to at least three logarithmically graded doses with ten mice at each dose level for each compound and calculating according to the From the results shown in the above tables it can be seen that five of-the compounds of the present invention are more active than the seven reference compounds. Most inportantly, the safety margins of eight of the novel compounds of the present invention are beturacil thioureas of the present invention and various.

methods of purification of these novel compounds other than recrystallization from methanol will be apparent to those skilled in the art. So also, the reaction conditions of temperature, time and proportions of reactants can be modified from those illustrated in the specific examples. When solvent media is used for the synthesis of the uracil thioureas, it is preferred to use dimethylformamide at reflux temperature. When dimethylsulfoxide is used as solvent media, it is important to use a reaction temperature not above about 150C, since at substantially higher temperatures this solvent will act as an oxidizing agent to produce the aforementioned thiazolopyrimidines instead of the herein desired uracil thioureas. In this synthesis the 6-amino-l ,3 -dimethyl-uracil or 6-amino-l,3-dimethylthiouracil is generally reacted with about a molar equivalent or an excess of the isothiocyanate at reflux temperatures. An effective barbiturate antagonist dose of the uracil thioureas can be formulated in any conventional dosage form for administration, including admixtures with many solid and liquid diluents, carriers and adjuvants other than those previously described. These dosages can be administered to revive animals given an overdose of barbiturates, sedatives and hypnotics such as, for example, pentobarbital sodium, phenobarbital, phe- 6 nobarbital sodium, chloral hydrate and the like substances.

What is claimed is:

l. A uracil thiourea having the formula wherein X is selected from the group consisting of O and S, and wherein R is selected from the group consisting of lower alkyl having from 1 to 4 carbon atoms, allyl, methallyl and phenyl.

2. The uracil thiourea of claim 1 in which R is allyl and X is S.

3. The uracil thiourea of claim 1 in which X is O.

4. The uracil thiourea of claim 3 in which R is methyl.

5. The uracil thiourea of claim 3 in which R is ethyl.

6. The uracil thiourea of claim 3 in which R is allyl.

7. The uracil thiourea of claim 3 in which R is isopro- M 8. The uracil thiourea of claim 3 in which R is npropyl.

9. The uracil thiourea of claim 3 in which R is mathallyl.

10. The uracil thiourea of claim 3 in which R is isobutyl.

11. The uracil thiourea of claim 3 in which R is nbutyl.

12. The uracil thiourea of claim 3 in which R is phenyl. 

2. The uracil thiourea of claim 1 in which R is allyl and X is S.
 3. The uracil thiourea of claim 1 in which X is O.
 4. The uracil thiourea of claim 3 in which R is methyl.
 5. The uracil thiourea of claim 3 in which R is ethyl.
 6. The uracil thiourea of claim 3 in which R is allyl.
 7. The uracil thiourea of claim 3 in which R is isopropyl.
 8. The uracil thiourea of claim 3 in which R is n-propyl.
 9. The uracil thiourea of claim 3 in which R is mathallyl.
 10. The uracil thiourea of claim 3 in which R is isobutyl.
 11. The uracil thiourea of claim 3 in which R is n-butyl.
 12. The uracil thiourea of claim 3 in which R is phenyl. 